title: Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers.
abstract: Myc is one of the most commonly deregulated oncogenes in human cancer, yet therapies directly targeting Myc hyperactivation are not presently available in the clinic. The evolutionarily conserved function of Myc in modulating protein synthesis control is critical to the Myc oncogenic program. Indeed, enhancing the protein synthesis capacity of cancer cells directly contributes to their survival, proliferation, and genome instability. Therefore, inhibiting enhanced protein synthesis may represent a highly relevant strategy for the treatment of Myc-dependent human cancers. However, components of the translation machinery that can be exploited as therapeutic targets for Myc-driven cancers remain poorly defined. Here, we uncover a surprising and important functional link between Myc and mammalian target of rapamycin (mTOR)-dependent phosphorylation of eukaryotic translation initiation factor 4E binding protein-1 (4EBP1), a master regulator of protein synthesis control. Using a pharmacogenetic approach, we find that mTOR-dependent phosphorylation of 4EBP1 is required for cancer cell survival in Myc-dependent tumor initiation and maintenance. We further show that a clinical mTOR active site inhibitor, which is capable of blocking mTOR-dependent 4EBP1 phosphorylation, has remarkable therapeutic efficacy in Myc-driven hematological cancers. Additionally, we demonstrate the clinical implications of these results by delineating a significant link between Myc and mTOR-dependent phosphorylation of 4EBP1 and therapeutic response in human lymphomas. Together, these findings reveal that an important mTOR substrate is found hyperactivated downstream of Myc oncogenic activity to promote tumor survival and confers synthetic lethality, thereby revealing a unique therapeutic approach to render Myc druggable in the clinic.
authors.affiliation: School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Pourdehnad
authors.forename: Morgan L
authors.initials: ML
authors.lastname: Truitt
authors.forename: Imran N
authors.initials: IN
authors.lastname: Siddiqi
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Ducker
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.forename: Davide
authors.initials: D
authors.lastname: Ruggero
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D001583:Benzoxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors; D000068338:Everolimus; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001583:Benzoxazoles; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D039642:Eukaryotic Initiation Factors; D000068338:Everolimus; D010750:Phosphoproteins; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C499527:Eif4ebp1 protein, mouse; C489428:Myc protein, mouse; C546843:mTOR protein, mouse; C572449:sapanisertib; D000225:Adenine
keywords: MLN0128; eIF4E; eIF4EBP1; multiple myeloma